In contrast to the gastrointestinal tract, the mucosal immune system of the female genital tract displays immunologically distinct features, including the dominance of IgG instead of secretory IgA, and highly variable Ig levels that are influenced by the hormonally-regulated menstrual cycle. Furthermore, the female genital tract lacks mucosal lymphoepithelial inductive sites analogous to intestinal Peyer's patches. The phenotypes of lymphocytes resident in the female genital tract differ from those of the intestinal tract, with respect to the expression of mucosal homing receptors. Immunological evaluations of immune responses to HIV-1 in the female genital tract and other external secretions indicate that the dominant response to HIV-1 is associated with the IgG isotype, irrespective of the route of infection; IgA responses are usually of low magnitude. This proposal focuses on IgA responses to other antigens which may also be compromised as a consequence of HIV-1 infection due to the extensive depletion of CD4+ T cells, whose products are essential in the differentiation of B cells to IgA-secreting plasma cells and generation of antibody diversity. Based on our preliminary data, we hypothesize that due to the strong dependence of IgA production on CD4+ T cells, immune responses to antigens that stimulate vigorous IgA responses are markedly diminished, resulting in compromised mucosal defenses of HIV-1-infected women. To address this hypothesis, we propose to: 1) determine whether HIV-1-infected women display altered IgA, IgG, and IgM responses to mucosally encountered antigens, focusing on biologically active bacterial antigens which stimulate vigorous IgA responses in healthy individuals; 2) determine the presence and effector functions of HIV-1-specific antibodies in genital tract secretions. The ability of HIV-1-specific neutralizing and non- neutralizing antibodies to inhibit the infection of the female genital tract in tissue explants will be determined, in collaboration with Project 1, and antibody-dependent cell-mediated virus inhibition (ADCMVI) will be determined, in collaboration with Project 3; and 3) determine whether HIV-1 infection alters the expression of homing receptors on peripheral blood B and T cells with emphasis on those involved in selective distribution of these cells to the genital (a4|31) or intestinal (a4fJ7) tract, or lymph nodes (L-selectin). The integration of the results of these studies will ultimately elucidate mechanisms involved in altered humoral immune responses in the female genital tract of HIV-1-infected women. RELEVANCE (See instructions): Current studies demonstrate that the mucosal immune systems of the female genital and intestinal tracts, which are both primary sites of HIV entry, must be considered related, but markedly distinct compartments. These differences in the origin and homing of cells in these two locales due to the expression of receptors and other phenotypic markers, dominance of Ig isotypes, and magnitude and quality in immune responses must be considered in immunization strategies that would protect both female genital and intestinal tracts.